1. Field of the Invention
The present invention relates to methods and reagents for promoting smoking cessation. The present invention relates to methods and reagents for preventing smoking addiction. The present invention also relates to methods and reagents for treating nicotine addiction.
2. Background of the Invention
Smoking addiction is a complex phenomenon believed to involve cognition enhancement, psychological conditioning, stress adaptation, reinforcing properties and relief from withdrawal. Consequently, providing therapeutic treatment for smoking addiction is an extremely difficult challenge.
Tobacco products, including cigarettes, cigars, pipes and smokeless tobacco, can cause a variety of well-recognized health problems. From a public health perspective, it is desirable to stop consuming tobacco products, especially in the form of smoking. However, some individuals cannot quit smoking tobacco products, in spite of focused attempts to succeed. One major factor in the difficulty of quitting smoking is the presence of nicotine in tobacco.
Nicotine can produce a myriad of behavioral effects and is unquestionably one of the most popular and powerful reinforcing agents. In addition, smoking, arguably the vehicle of choice for nicotine delivery, may cause a variety of well-recognized health problems. For these reasons it has sometimes been desirable to cease consumption of nicotine. However, for some, the termination of nicotine consumption can not be accomplished, in spite of focused attempts to succeed.
One method for assisting smoking cessation is to reduce consumption over time. For complex reasons, this method is not always entirely successful. One method for assisting smoking cessation is to provide an alternate delivery vehicle for nicotine. Such delivery vehicles include oral preparations such as gums, and transdermal vehicles such as skin patches.
Another method for assisting smoking cessation is to replace the nicotine signal from tobacco with a substitute reinforcer. Bupropion is used to promote smoking cessation and it may act as a substitute reinforcer.
Nicotine antagonists have been considered as an approach to smoking cessation. A nicotine antagonist would block the reinforcing signal from nicotine that creates and maintains the addiction to smoking. Over time, the smoker would dissociate the physical and psychological aspects of smoking. For example, mecamylamine has been used to promote smoking cessation, although it is generally ineffective alone. Another approach is to administer an antagonist, e.g., mecamylamine, together with nicotine replacement therapy. Compounds which act as nicotine substitutes and block nicotine""s effects would be preferred smoking cessation reagents.
In spite of the known methods for treating smoking addiction, there remains a lack of generally effective means of treating and/or preventing smoking addiction. Accordingly, there remains a strong need for methods and reagents for treating smoking addiction.
Both the psychological and physiological effects of tobacco smoke are attributed to nicotine. Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central and peripheral nervous systems including several regions of the brain. Two major classes of nAChRs, xcex14xcex22 and xcex17 have been identified in rat and human brains. The possibility exists that specific subtypes mediate specific functions, especially as this relates to nicotine addiction. Thus, the availability of a variety of ligands that bind with high affinity and selectivity for each subtype are needed. It is also desirable to have both agonists and antagonists since the role of nAChRs in addiction is not known.
Epibatidine is a nicotinic agonist whose biological effects appear to be mediated by xcex14xcex22 nAChRs. The high potency of epibatidine for xcex14xcex22 nAChRs makes this agent a very useful lead compound for the development of new ligands for studying this nicotinic subtype. Such epibatidine analogs may be potent and/or selective for xcex14xcex22 receptors could provide a therapeutic for treatment of in addition to nicotine dependence, pain, and other neurological disorders.
It is an object of the present invention to provide methods of training a smoker to quit smoking.
It is another object of the invention to provide compounds which can be used to train a smoker to quit smoking.
It is an object of the present invention to provide a method of training a smoker to quit smoking, comprising administering to a smoker in need thereof an effective amount of a compound represented by formula (I): 
wherein
A1 and A2 are each, independently, H, xe2x80x94OH, xe2x80x94N(R)C(xe2x95x90NR)N(R)2 or xe2x80x94N(R)2; or
A1 and A2 together form xe2x95x90O, xe2x95x90NOR, xe2x95x90NR, xe2x80x94Oxe2x80x94NRxe2x80x94, xe2x80x94NRxe2x80x94Oxe2x80x94 or xe2x80x94NRxe2x80x94NRxe2x80x94;
each Q is, independently, Cxe2x80x94X or N, with the proviso that at least one Q is N and at least one Q is Cxe2x80x94X;
each X is, independently, H, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, xe2x80x94OH, xe2x80x94OR, xe2x80x94CH2xe2x80x94CO2R, xe2x80x94COxe2x80x94R, xe2x80x94CO2R, xe2x80x94N(R)2, xe2x80x94NRxe2x80x94COxe2x80x94R, xe2x80x94COxe2x80x94N(R)2, xe2x80x94NRCO2R, xe2x80x94SO3CF3, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CF3, xe2x80x94CHxe2x95x90CHY, or xe2x80x94CN;
Y is a halogen; and
each R is, independently, H, alkyl, alkenyl, alkynyl, aryl, or aralkyl;
or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method of training a smoker to quit smoking, comprising administering to a smoker in need thereof an effective amount of a compound represented by formula (II): 
wherein
A3 is xe2x80x94R, xe2x80x94N(R)2, xe2x80x94C(xe2x95x90NR)N(R)2, or xe2x80x94OR; and
R and Q are as defined above,
or a pharmaceutically acceptable salt thereof.
It is also an object of the present invention to provide a method of training a smoker to quit smoking, comprising administering to a smoker in need thereof an effective amount of a compound represented by formula (III): 
wherein
Z is xe2x80x94(CH2)mxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mN(R)xe2x80x94, xe2x80x94N(R)(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94(CH2)mSxe2x80x94, (CH2)mCHxe2x95x90CHxe2x80x94, or xe2x80x94(CH2)mCxe2x89xa1Cxe2x80x94;
m is 1, 2, 3 or 4; and
R and Q are as defined above,
or a pharmaceutically acceptable salt thereof.
The present invention is also directed to the compounds represented by formula (I) and (III) above.
The present invention is also directed to the compounds represented by formula (II) above in which at least one Q group is Cxe2x80x94X in which X is aryl.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description.